Mutagenicity of Tocopheryl Quinones: Evolutionary Advantage of Selective Accumulation of Dietary a-Tocopherol

Abstract

We have shown that phenolic antioxidant tocopherols are oxidized to nonarylating α-tocopheryl quinone (α-TQ) and arylating γ- and δ-TQ electrophiles. The arylating quinones stimulate apoptosis and are highly cytotoxic in mammalian cells. Some xenobiotic phenolic antioxidants are mutagens, and it has been suggested that their arylating quinone metabolites are the active agents in mutagenesis related to carcinogenesis. We found that neither α- nor γ-TQ was directly genotoxic in supercoiled-to-nicked circular DNA conversions, but these agents interacted with the cytomegalovirus reporter-driven plasmid and enhanced luciferase transfection, with γ-TQ >?α-TQ. The Ames test, using γ-TQ and a number of Salmonella strains, showed no evidence of bacterial mutagenesis. γ-TQ was highly cytotoxic and α-TQ slightly cytotoxic in eukaryocyte AS52 cells. A guanosine phosphoribosyltransferase gene assay showed that γ-TQ was highly mutagenic and α-TQ slightly mutagenic in AS52 cells. A review of the literature identified associations where a decrease in dietary γ-tocopherol (γ-T) diminishes and an increase in dietary γ-T and its quinone enhances carcinogenicity. Humans and other omnivores selectively accumulate α-tocopherol, even though γ-T is their principal dietary tocopherol. We suggest that this selectivity confers an evolutionary advantage by limiting tissue γ-T, a putative precursor of the mutagen γ-TQ.